The preferred first line of care for treating localized solid tumors is surgical removal, where the benefit of removing all of the cancer and surrounding tissue is balanced against the resultant morbidity to the patient. Given that microscopic disease can be present despite a complete surgical resection, surgery is often “augmented” with radiation and/or chemotherapy in an attempt to prevent recurrent cancer. Despite this aggressive approach, tumor recurrence is a major concern following primary treatment for many cancers including head, breast, lung, colon, rectal, and pancreatic malignancies. Recurrence can occur at a distant site due to cell migration or metastasis, pre-existing micrometastases missed at the time of the initial diagnosis, or microscopic disease that remains near the resection margins of the primary tumor.
In patients unable to tolerate surgery or if there is a particularly high risk of recurrence due to aggressive pathology or positive margins, treatment commonly includes external radiation therapy or chemotherapy. Several large clinical trials have indicated a potential survival benefit with adjuvant chemotherapy compared to observation alone following surgery for early stage lung cancer, however, such treatment has not become the standard of care as the overall benefit is small due to the significant adverse effects associated with the systemic therapy. Paclitaxel is one of the most widely used chemotherapeutic agents, often utilized as a first-line therapy for breast, ovarian, and non-small cell lung cancers. The poor aqueous solubility of paclitaxel requires formulation with a mixture of Cremophor EL and ethanol for intravenous delivery, but acute hypersensitivity reactions (41%) and nerve damage (60%) leading to abnormal sensation and pain in the extremities, significantly limit clinical effectiveness. Other common side effects due to systemic administration include low blood counts (70-90% of patients) with the resultant risk of infection, hair loss (87%), decreased oxygen exchange, fatigue or muscle/bone pain (60%), nausea and vomiting (52%), diarrhea (38%), mouth sores (31%) and bleeding (14%).
Localized drug delivery has been identified as a preferred mode of treatment for a number of medical conditions including but not limited atherosclerosis (stents) and control of inflammation/wound healing. In particular, localized drug delivery is an attractive and actively investigated medium for the treatment of most localized forms of cancer. Drugs, contrast agents, and targeting moieties have been covalently-bound or entrapped by a polymer in the form of prodrugs, micelles, particles, or bulk material in an attempt to both increase solubility and localize delivery to tumors via systemic targeting or local delivery. A drug delivery platform that locally delivers therapeutic doses of drug directly to the site of disease, while also significantly diminishing the systemic toxicity associated with intravenous chemotherapy and external radiation, offers significant advantages over all currently available approaches to prevent local tumor growth or recurrence. Loco-regional delivery is particularly beneficial in situations where: 1) therapeutic levels of chemotherapy are not achievable due to poor aqueous solubility, non-ideal pharmacokinetics or biodistribution, 2) systemic treatment approaches are ineffective or highly toxic, 3) the incidence of local recurrence does not warrant universal treatment of all patients with a highly morbid systemic therapy, or 4) surgical resection of recurrent disease is not an option and alternative rescue therapies are generally unsuccessful.
A drug delivery device intended to prevent local recurrence must be localized to the resection margin and deliver chemotherapy directly to the site of potential recurrent disease. Ideally, the delivery platform will: (1) preserve the activity of the embedded drug molecules over the therapeutic lifetime; (2) release drug in a controlled and sustained manner to ensure adequate diffusion and uptake into cancer cells; (3) kill microscopic malignant disease in the local environment of the resection margins; (4) invoke minimal damage to healthy tissue; (5) eliminate side effects due to systemic circulation of the chemotherapeutic drug; and (6) be biocompatible. The delivery platform must ultimately reduce or eliminate the incidence of microscopic malignant disease at or near the site of resection, while preserving surrounding healthy lung tissue. Notably, both the choice of polymer and drug can profoundly affect release behavior through variations in thermal properties, relative crystallinity, and hydrophobicity of the polymer and partition coefficient, molecular weight, and loading of the drug.
Today, there are few delivery devices reported for the prevention of local growth of early or residual cancer. First, paclitaxel-loaded thermosensitive chitosan-based hydrogels, developed by Leroux et. al., were implanted four days after tumor cell inoculation and demonstrated a significant decrease, but not complete inhibition, of tumor growth. Second, Matsuda et. al. created a polyurethane-based pouch which was sutured subcutaneously in tumor-bearing mice and loaded with gemcitabine three days after tumor inoculation. Four of six mice supporting loaded devices had no observable tumor mass during the 30 day observation period, but the remaining two mice developed tumors at a rate comparable to the control mice. Third, cross-linked chitosan hydrogels have also been loaded with a radioisotope to deliver localized radiotherapy for prevention of tumor recurrence in breast cancer. Implants loaded with 131I-norcholesterol were co-implanted with 4T1 metastatic mammary mouse tumor cells to simulate microscopic residual disease and tumor growth was prevented in 69% of the mice.
The most established local chemotherapy delivery device to date is used in the treatment of malignant glioma, an aggressive brain cancer that often recurs near the resection margins of the primary, tumor. Commercially manufactured by MGI Pharma under the brand name GLIADEL®, the device delivers the chemotherapeutic carmustine from a rigid biodegradable polyanhydride wafer placed near the resection margins. The wafers have a modest impact on the survival of treated patients, but patients report a markedly higher quality of life compared to those treated by conventional systemic chemotherapy.
Although all of these materials are suitable for the delivery of anticancer agents locally, there is an absence of delivery systems that can be attached directly to tissue surfaces for prolonged periods of drug release. Hydrogel-based systems have been developed that are elastic in nature and adhere directly to tissues, but these materials release most of their loaded drug over a short duration, from hours to a couple days, and generally degrade or swell in the short term. The GLIADEL® wafer is a polymer matrix that is directly deposited in the resection cavity following surgical treatment of malignant glioma, and also releases the majority of its loaded drug over several days. Drug-eluting stents are effective at delivering anti-proliferative agents for days to weeks, and they remain fixed in place to treat diseased tissue locally, but they are not designed to be compliant to a range of tissue shapes and surfaces.